The present invention relates to a process for preparing 4,6-dichloropyrimidine from 4-chloro-6-methoxypyrimidine. 4,6-Dichloropyrimidine is a valuable intermediate for preparing crop protection agents.
A number of processes for preparing 4,6-dichloropyrimidine are known, see, for example, WO 96/23776, EP-A-697 406, EP-A-745 593, WO 95/29166, DE-A19 53 129 and GB 2 325 224. However, these processes always start from 4,6-dihydroxypyrimidine.
It is also known (see Res. Discl. n 391, 690-691 (1996)) that 4,6-dichloropyrimidine can be reacted by reacting 4-chloro-6-methoxypyrimidine with a chlorinating agent of the formula R3PCl2. The chlorinating agent can be employed as such or be prepared in situ from a compound of the formula R3Pxe2x95x90O and phosgene. It is additionally described therein that 4-chloro-6-methoxypyrimidine does not react with phosphorus oxychloride. The disadvantage of this process is that, as a rule, only a very incomplete reaction can be achieved and thus 4,6-dichloropyrimidine is obtainable only in low yields and low degrees of purity.
A process for preparing 4,6-dichloropyrimidine which is characterized in that 4-chloro-6-methoxypyrimidine is reacted with an acid chloride in the presence of a hydrogen halide has now been found.
Suitable acid chlorides are organic and inorganic acid chlorides, for example PCl3, POCl3, PCl5, Rxe2x80x94PCl2, Rxe2x80x94PCl4, Rxe2x80x94POCl2 and R3PCl2, where R represents optionally substituted C6-C10-aryl or optionally substituted C1-C10-alkyl, acid chlorides of the formula Rxe2x80x2xe2x80x94COxe2x80x94Cl with Rxe2x80x2= chlorine, C1-C10-alkoxy, C6-C10-aryloxy, xe2x80x94OCCl3, xe2x80x94COxe2x80x94Cl, C5-C11-heteroaryloxy with 1 to 3 heteroatoms from the group of N, O and S, whereas the alkoxy, aryloxy and hetaryloxy radicals may optionally be substituted, and SOCl2.
It is furthermore possible to generate the required acid chloride in situ. For example, R3PCl2 can be generated from R3P and chlorine or from R3Pxe2x95x90O and a chlorinating agent, for example PCl3, phosgene or SOCl2.
Suitable examples of hydrogen halides are: hydrogen chloride, hydrogen bromide and hydrogen iodide. Hydrogen chloride is preferred. The use of mixtures of hydrogen halides is also possible.
Hydrogen chloride can, for example, be employed as such in the form of a gas or be generated in situ from an excess of added acid chloride and a protic compound. A wide variety of protic compounds which cause no unwanted side reactions in the reaction mixture are suitable. Examples which may be mentioned are: water, alcohols and organic and inorganic acids.
It is preferred to add gaseous hydrogen chloride or generate it in situ. Gaseous hydrogen chloride is particularly preferably employed.
It is preferred to employ in the process of the invention at least 1 mol of acid chloride per mole of 4-chloro-6-methoxypyrimidine. It is preferable to employ 1.1 to 20 mol, particularly preferably 1.5 to 10 mol, of acid chloride per mole of 4-chloro-6-methoxypyrimidine. If the acid chloride is also employed as solvent or as starting material for the in situ generation of hydrogen halide, the preferred minimum amount of acid chloride is, of course, correspondingly higher.
In addition, at least 1 mol of hydrogen halide is employed per mole of 4-chloro-6-methoxypyrimidine. However, an excess of hydrogen halide is advisable to achieve a high conversion.
It is preferable to employ 1.1 to 25 mol of hydrogen halide, particularly preferably 2 to 10 mol of hydrogen halide, per mole of 4-chloro-6-methoxypyrimidine.
If it is wished to generate the abovementioned amounts of hydrogen halide in situ from a protic compound and an acid chloride, the protic compound is employed in amounts such that it generates the abovementioned amounts of hydrogen halide, that is to say, for example, to generate 1 mol of hydrogen chloride for example 0.5 mol of water or 1.0 mol of methanol is employed. In this case, it is also preferred to employ additional amounts of acid chlorides which are equivalent to the amounts of hydrogen chloride to be generated, for example to generate 1 mol of hydrogen chloride additionally 0.33 mol of phosphorus oxychloride or additionally 0.5 mol of thionyl chloride.
If an acid chloride which is liquid under the reaction conditions is used, it is possible to dispense with the addition of a solvent. Suitable solvents in principle are those which do not adversely affect the reaction to be carried out. Examples of solvents are aliphatic solvents such as alkanes, cycloalkanes and halogenoalkanes, aromatic solvents such as benzene, toluene, xylenes, chlorobenzene, chlorotoluenes, dichlorobenzenes, benzotrifluoride and p-chlorobenzotrifluoride, it being possible for the aliphatic and aromatic solvents optionally to be substituted further, nitrites such as acetonitrile and benzonitrile, N-containing solvents such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone and cyclic ureas and ethers and polyethers of a wide variety of types.
The process of the invention can be carried out, for example, at temperatures in the range 0 to 200xc2x0 C., preferably at 20 to 175xc2x0 C., particularly preferably at 30 to 150xc2x0 C. The pressure is not critical. It can be, for example, 0.1 to 50 bar, preferably 0.5 to 5 bar. Atmospheric pressure is particularly preferred.
It is possible to employ catalysts known in principle from the area of chemical reactions with acid chlorides, for example amides such as dimethylformamide, amines such as pyridine, morpholine or 1,8-diazobicyclo[5.4.0]undec-7-ene (=DBU) or phosphorus compounds such as triphenylphosphine or triphenylphosphine oxide.
Catalysts of these types can be employed, for example, in amounts of from 0.1 to 10 mol %, based on the 4-chloro-6-methoxypyrimidine. Preference is given to no additions of catalyst.
The process of the invention can be carried out in a wide variety of embodiments, for example batchwise, semicontinuously, continuously or semibatchwise (concerning the latter, see DE-A 195 31 299).
For example, acid chloride and, where appropriate, solvent can be added to solid or molten 4-chloro-6-methoxypyrimidine and, at the desired reaction temperature, either hydrogen halide can be passed in or a protic compound can be metered in. After the reaction is complete, the reaction mixture can be worked up in a manner known per se, for example
a) by adding water to the reaction mixture and removing the 4,6-dichloropyrimidine,
b) by distilling the complete reaction mixture,
c) by first rechlorinating the used acid chloride with, for example, PCl3/Cl2 or PCl5 and subsequently distilling and
d) by directly extracting the 4,6-dichloropyrimidine from the reaction mixture with a suitable solvent and subsequently distilling the extract.
It is possible to choose for the rechlorination according to c) a semibatchwise procedure. The procedure for this can, for example, be such that 4-chloro-6-methoxypyrimidine and, for example, phosphorus oxychloride are heated to the reaction temperature, gaseous hydrogen chloride is passed in and, after partial conversion, for example 25 to 60 mol %, the appropriate amount of PCl3 or a slight excess (for example of 5 to 10 mol %) is added, and the appropriate amount of chlorine is passed in. The passing in of hydrogen chloride is then continued, possibly interrupted once more and again rechlorinated with PCl3 and chlorine in the amount corresponding to the conversion or a slight excess. With such a procedure for the process of the invention, the reaction mixture contains 4,6-dichloropyrimidine and only small residues (generally less than 2 mol %) of 4-chloro-6-methoxypyrimidine, phosphorus oxychloride, PCl3 and hydrogen chloride after the end of the conversion and final rechlorination with PCl3/Cl2. This mixture can be worked up simply by distillation. It is possible with this procedure, for example, to add all the PCl3 at the start of the passing-in of hydrogen chloride or in the first rechlorination.
The process of the invention represents a fundamentally novel method for preparing 4,6-dichloropyrimidine. In contrast to the disclosed literature, even simple acid chlorides such as phosphorus oxychloride react with 4-chloro-6-methoxypyrimidine directly to give 4,6-dichloropyrimidine if hydrogen halides are present.
The process of the invention can be carried out industrially without difficulty. Simply by passing in a hydrogen halide, in the simplest case hydrogen chloride, or metering in a protic compound, in the simplest case water, it is possible to react acid chlorides, in the simplest case phosphorus oxychloride, with 4-chloro-6-methoxypyrimidine to form 4,6-dichloropyrimidine. It is possible on use of liquid acid chlorides to do without solvents, which makes the subsequent workup extremely simple. The process of the invention additionally represents a considerable advance compared with the prior art described in Res. Discl. loc. cit. The two examples mentioned therein show that only incomplete conversion of 4-chloro-6-methoxypyrimidine to 4,6-dichloropyrimidine has taken place therein. This is particularly disadvantageous because 4,6-dichloropyrimidine and 4-chloro-6-methoxypyrimidine can be separated only very poorly by distillation. Under the conditions according to the invention, especially in the presence of hydrogen halide, the conversion takes place considerably faster and completely or nearly completely.